title: Design of substituted imidazolidinylpiperidinylbenzoic acids as chemokine receptor 5 antagonists: potent inhibitors of R5 HIV-1 replication.
abstract: The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure-activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.
authors.affiliation: LGCR Unit, Sanofi , 153 Second Avenue, Waltham, Massachusetts 02451, United States.
authors.forename: Renato
authors.initials: R
authors.lastname: Skerlj
authors.forename: Gary
authors.initials: G
authors.lastname: Bridger
authors.forename: Yuanxi
authors.initials: Y
authors.lastname: Zhou
authors.forename: Elyse
authors.initials: E
authors.lastname: Bourque
authors.forename: Ernest
authors.initials: E
authors.lastname: McEachern
authors.forename: Markus
authors.initials: M
authors.lastname: Metz
authors.forename: Curtis
authors.initials: C
authors.lastname: Harwig
authors.forename: Tong-Shuang
authors.initials: TS
authors.lastname: Li
authors.forename: Wen
authors.initials: W
authors.lastname: Yang
authors.forename: David
authors.initials: D
authors.lastname: Bogucki
authors.forename: Yongbao
authors.initials: Y
authors.lastname: Zhu
authors.forename: Jonathan
authors.initials: J
authors.lastname: Langille
authors.forename: Duane
authors.initials: D
authors.lastname: Veale
authors.forename: Tuya
authors.initials: T
authors.lastname: Ba
authors.forename: Michael
authors.initials: M
authors.lastname: Bey
authors.forename: Ian
authors.initials: I
authors.lastname: Baird
authors.forename: Alan
authors.initials: A
authors.lastname: Kaller
authors.forename: Maria
authors.initials: M
authors.lastname: Krumpak
authors.forename: David
authors.initials: D
authors.lastname: Leitch
authors.forename: Michael
authors.initials: M
authors.lastname: Satori
authors.forename: Krystyna
authors.initials: K
authors.lastname: Vocadlo
authors.forename: Danielle
authors.initials: D
authors.lastname: Guay
authors.forename: Susan
authors.initials: S
authors.lastname: Nan
authors.forename: Helen
authors.initials: H
authors.lastname: Yee
authors.forename: Jason
authors.initials: J
authors.lastname: Crawford
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Trevor
authors.initials: T
authors.lastname: Wilson
authors.forename: Bryon
authors.initials: B
authors.lastname: Carpenter
authors.forename: David
authors.initials: D
authors.lastname: Gauthier
authors.forename: Ron
authors.initials: R
authors.lastname: Macfarland
authors.forename: Renee
authors.initials: R
authors.lastname: Mosi
authors.forename: Veronique
authors.initials: V
authors.lastname: Bodart
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wong
authors.forename: Simon
authors.initials: S
authors.lastname: Fricker
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D057809:HEK293 Cells; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D048289:Imidazolidines / Q000737:chemistry; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000821:virology; D008956:Models, Chemical; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D001565:Benzoates; D065100:CCR5 Receptor Antagonists; D007093:Imidazoles; D048289:Imidazolidines; D010880:Piperidines; D019713:Receptors, CCR5